In neurodegenerative disorders such as Alzheimers, Parkinsons and Huntingtons diseases, neurons may die by a form of programmed cell death called apoptosis. A major effort in the Cellular and Molecular Neurosciences section of the Laboratory of Neurosciences is aimed at establishing what triggers apoptosis in neurodegenerative disorders and how neuronal degeneration might be prevented by targeting specific molecular events in the process of apoptosis. Studies of cultured neurons demonstrated that activation of glutamate receptors can induce a transient damage to DNA which is rapidly repaired as the result of calcium-mediated upregulation of the DNA repair protein APE1. In addition, we have identified a mitochondrial uncoupling protein (UCP4) that can protect neurons in models relevant to stroke and Alzheimers disease by a mechanism involving suppression of oxidative stress and stabilization of cellular calcium homeostasis. We have also established roles for brain-derived neurotrophic factor (BDNF) in preventing the apoptosis of neurons produced from stem cells in the hippocampus, a finding that suggests the possibility of increasing the capacity of the brain to replace lost and damaged neurons. In other studies we have found that newly generated neurons are highly sensitive to DNA damage-induced apoptosis because they have low levels of telomerase and the telomere-associated protein TRF2. Preclinical studies have shown that intravenous immunoglobulin and gamma-secretase inhibotors are effective in stroke models. More recently, we have shown that neurons express several toll-like receptors, and have provided evidence that activation of two of these receptors (TLR2 and TLR4) can trigger apoptosis in cell culture and animal models of Alzheimer's disease and stroke. In other studies we have revealed important roles for plasma membrane redox enzymes in protecting neurons against apoptosis in experimental models of aging and neurodegenerative disorders. Novel mechanisms of protecting neurons against apoptosis in experimental models of stroke and Alzheimer's disease have been discovered. First, we found that the plasma membrane redox enzymes, including NQO1 can protect neurons against amyloid toxicity. Second, we found that the calcium channel inhibitor pregabalin can protect neurons against apoptosis in cell cutlure and animal models of stroke. These findings suggest novel approaches for improving the outcome of a stroke or suppressing the neurodegenerative process. Abnormally prolonged exposure to glutamate causes neuronal injury, and such excitotoxicity has been implicated in many acute and chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases. Interestingly, although glutamate-induced Ca(2+) influx can cause DNA damage by a mitochondrial reactive oxygen species-mediated mechanism, the Ca(2+) simultaneously activates CREB, resulting in up-regulation of the DNA repair and redox protein apurinic/apyrimidinic endonuclease 1. Here, we review connections between physiological or aberrant glutamate receptor activation, Ca(2+)-mediated signaling, oxidative DNA damage and repair efficiency, and neuronal vulnerability. We conclude that glutamate signaling involves an adaptive cellular stress response pathway that enhances DNA repair capability, thereby protecting neurons against injury and disease. Ceruloplasmin (Cp) is an essential ferroxidase that plays important roles in cellular iron trafficking. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability. Brain iron dyshomeostasis is observed during normal aging, as well as in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, coincident with areas more susceptible to insults. Because of their high metabolic demand and electrical excitability, neurons are particularly vulnerable to ischemic injury and death. We therefore set out to look for abnormalities in the brain of young adult mice that lack Cp. We found that iron levels in the striatum and cerebral cortex of these young animals are significantly lower than wild-type (WT) controls. Also mRNA levels of the neurotrophin brain derived neurotrophic factor (BDNF), known for its role in maintenance of cell viability, were decreased in these brain areas. Chelator-mediated depletion of iron in cultured neural cells resulted in reduced BDNF expression by a posttranscriptional mechanism, suggesting a causal link between low brain iron levels and reduced BDNF expression. When the mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage in Cp-deficient mice compared to WT controls. Our data indicate that lack of Cp increases neuronal susceptibility to ischemic injury by a mechanism that may involve reduced levels of iron and BDNF. Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases. The mechanisms that lead to ER stress and whereby ER stress contributes to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies. We found that knockdown of Herp (Homocysteine-inducible ER stress protein), an ER stress-inducible protein with an ubiquitin-like (UBL) domain, aggravates ER stress-mediated cell death induced by mutant -synuclein (Syn) that causes an inherited form of Parkinson's disease (PD). Functionally, Herp plays a role in maintaining ER homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca(2+) release channels. Furthermore, knockdown or pharmacological inhibition of ER Ca(2+) release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca(2+) channels promotes a protracted ER stress with the consequent activation of ER stress-associated apoptotic pathways. Collectively, these data establish a causative link between impaired ER Ca(2+) homeostasis and chronic ER stress in the degenerative cascades induced by mutant Syn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca(2+) homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca(2+)-stabilizing action. We previously showed that calorie restriction ameliorated Huntington's disease (HD) pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of Sirt1, a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in BDNF concentrations and the signaling of its receptor, TrkB, and restores dopamine concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian HD models and open new avenues for the development of neuroprotective strategies in HD.